Dosage control for drug delivery system

ABSTRACT

A method for delivering intravenous drugs to a patient comprising programming a drug delivery system, including a controller and an infusion pump, with a maintenance rate or a loading dose for a drug and causing the drug delivery system to (a) calculate a loading dose based on the maintenance rate or a maintenance rate based on the loading dose, (b) administer the loading dose of the drug to the patient to rapidly achieve a desired level of effect, and (c) administer the drug at a first maintenance rate to maintain the level of effect.

CROSS REFERENCE TO RELATED PATENT APPLICATION

This is a continuation of U.S. patent application Ser. No. 10/886,255,filed on Jul. 7, 2004.

FIELD OF THE INVENTION

The present invention relates generally to drug delivery systems, andmore particularly to a method of calculating a drug infusion profile fora drug delivery system. While the invention can be used in administeringa variety of intravenous drugs it is particularly useful as ananesthetic delivery system.

BACKGROUND OF THE INVENTION

Three conditions or objectives control the administration of ananesthetic, namely, to rapidly produce the desired pharmacologic effect(hypnosis, analgesia, etc.); to maintain the desired effect throughoutthe medical procedure; and to enable the patient to recover quickly fromthe effect following completion of the procedure.

In order to achieve the objective of rapidly inducing the desiredanesthetic effect, the anesthesiologist typically delivers a so called“Loading Dose.” A Loading Dose is a bolus (mg/kg, mg, etc.) of drug thatrapidly brings the patient to a desired level of effect. In order tomaintain the level of effect the anesthesiologist often uses an infusionpump to deliver a so called “Maintenance Rate.” A Maintenance Rate is aconstant infusion rate (μg/kg/min, mg/min, etc.) required to maintainthe patient at a certain target, in this embodiment anesthetic, effect.The anesthesiologist may have to titrate this Maintenance Rate duringthe procedure as the patient's anesthetic needs change. A method thatallows for rapidly adjusting the patient's level of effect is desired.Finally, in order to enable the patient to recover quickly from theanesthetic following completion of the procedure, the anesthesiologistattempts to deliver as little drug as needed. This can include taperingdown the Maintenance Rate prior to the end of the procedure.

The term “anesthesia” is used herein to refer to the continuum ofhypnosis and analgesia, achieved via anesthetic drugs, from anxiolysisthrough general anesthesia. In producing a level of anesthesia known asconscious sedation, as practiced by endoscopists, the anesthetic(s) istypically delivered through frequent boluses. This technique results invarying depths of anesthesia throughout the procedure. At times thepatient may be so heavily anesthetized as to be classified in generalanesthesia. At other times the patient may be under-anesthetized andexhibit pain and agitation. A patient responding to pain isuncooperative, making the procedure more difficult. As a result, theclinician tends to err on the over-anesthetized side. In addition toplacing the patient at greater risk for adverse events,over-anesthetizing causes the patient's recovery from anesthesia to bemuch longer. Accordingly, a method is desired that enables the clinicianto control the level of anesthesia without over- or under-anesthetizingthe patient.

The term “sedation drug” is used herein to refer to the classes of drugsemployed by anesthesiologists in inducing sedation including hypnoticsand analgesics. Propofol and remifentanil are preferred drugs forsedation, principally due to their rapid onset and offset. However, thisrapid action presents additional concerns for someone using anintermittent bolus technique, as typically done bynon-anesthesiologists. With a rapid onset/offset more frequent boluseswill be required. Consequently, anesthesiologists often use infusionpumps to continuously deliver these rapid action sedation drugs.However, non-anesthesiologists are not familiar with pharmacokinetic(PK) principals, and will have difficulty determining a LoadingDose/Maintenance Rate combination that will both rapidly achieve andmaintain the desired level of anesthesia. The Anesthetic Delivery System(ADS) is intended to enable a non-anesthesiologist to safely andeffectively use these rapid action anesthetic agents typically reservedfor use by anesthesiologists.

What is desired is an algorithm that will allow the clinician to programan ADS with a desired maintenance rate, selected by the clinician tomaintain a desired level of anesthesia, and then the ADS automaticallycalculates the appropriate sized loading dose based on thepharmacokinetics of the chosen sedation drug. The loading dose is thendelivered by the ADS to rapidly achieve the level of sedation,immediately followed by a constant infusion of the sedation drug at themaintenance rate, to maintain the level of anesthesia. Moreover, amethod is desired where the patient's level of anesthesia is rapidlyadjusted, each time the clinician changes the maintenance rate, inresponse to the patient's changing anesthetic needs. Specifically, whatis needed is an ADS that integrates the initiation and maintenance ofanesthesia in an equation so that the appropriate sized loading dose maybe calculated and administered to rapidly bring the patient's depth ofanesthesia to a level maintained by the programmed maintenance rate.Further, when a change in the maintenance rate is requested, the dosagecontroller (DC) can calculate an incremental loading dose to rapidlyachieve the new level of anesthesia.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides a method of drug infusion formaintaining or rapidly adjusting a patient's level of anesthesiacomprising programming an automated drug delivery system with amaintenance rate (MR); causing the drug delivery system to calculate theloading dose (LD) using a formula that relates loading dose andmaintenance rate; the drug delivery system infusing the loading doseinto patient to achieve a desired level of anesthesia and administeringthe drug at the maintenance rate to maintain the level of anesthesia.

In another embodiment, the invention provides a method of drug infusionfor maintaining or rapidly adjusting a patient's level of anesthesiacomprising the clinician programming an automated drug delivery systemwith a loading dose (LD); causing the drug delivery system to calculatethe maintenance rate (MR) using a formula that relates loading dose andmaintenance rate; the drug delivery system infusing the loading doseinto the patient to achieve a level of anesthesia and administering thedrug at the maintenance rate to maintain the level of anesthesia.

In a further embodiment, the level of anesthesia is rapidly adjustedwhen the clinician programs a new maintenance rate, by a method thatfurther comprises: calculating the cumulative loading dose based on thedrug already administered to the patient; calculating a new loading dosebased on the cumulative loading dose and a new maintenance rate based ona formula relating loading dose and maintenance rate; the ADS infusingthe new loading dose into patient to achieve the new level of anesthesiaand the administering the drug at the desired new maintenance rate tomaintain the new level of anesthesia.

Still a further embodiment is a drug delivery system that includes aninfusion pump and a controller and is programmed to control infusion asdescribed herein. In one embodiment, the system includes sensors formonitoring patient physiology and can be programmed to discontinueadministering the drug if adverse physiology or trends are detected.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a drawing of the Automated Response System (ARM) utilized inan embodiment of the invention.

FIG. 2 is a collection of flow charts (FIGS. 2A-2F) for a DC programuseful in accordance with an embodiment of the invention.

FIGS. 3 and 4 are graphs illustrating the determination of a rampedinfusion rate for a loading dose that culminates in the maintenancerate.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of illustration, the invention is explained using thedelivery of propofol to achieve and maintain a level of anesthesiareferred to as conscious sedation. However, the invention can be appliedto any intravenous drug where it is appropriate to deliver a loadingdose followed by a maintenance infusion. The equations will be adjustedfor different pharmacokinetics (loading dose/maintenance raterelationships) for these other drugs. Examples of classes of drugs inaddition to sedation drugs that can be administered in accordance withthe invention are antibiotics, pain management drugs, cardiovasculardrugs, anticancer drugs, and others.

A. Initiation of Sedation

An anesthetic drug such as propofol provides labeling recommendationsfor initiating sedation (loading dose)—0.0 to 0.5 mg/kg, and infusionrates for maintaining the patient's level of sedation (maintenancerate)—0.0 to 75 μg/kg/min. DC is designed to correlate these two ranges,such that a clinician simply enters a maintenance rate (MR) and DC willcalculate the appropriate loading dose (LD) with the following equationin the case of propofol:LD=0.5*W*(MR/75)where,

-   -   LD=loading lose (mg),    -   MR=maintenance rate (μg/kg/min),    -   W=weight (kg) of the patient    -   0.5=0.5 mg/kg    -   75=75 μg/kg/min.

For other drugs, and application, similar correlations can be developed.While these correlations will often be defined in terms of the weight ofthe patient, this does not have to be true for all cases. Some drugs mayhave dosages that are less dependent or essentially independent ofpatient weight for typical patients. The equation that has beendeveloped for propofol above is based on the maximum loading dose (0.5mg/kg) recommended for the drug and the therapy (e.g., conscioussedation) in which the drug is used and the maximum maintenance rate (75μg/kg/min). In this case the formula is a linear proportion or linearinterpolation. The clinician may select a maintenance rate correspondingto the level of anesthesia he desires to achieve, e.g., ASA guidelinesare drafted in terms of mild, moderate and deep anesthesia and based onthe ratio of that maintenance rate to the maximum maintenance raterecommended for that application of the drug, a loading dose isdetermined. Thus, in accordance with certain embodiments of theinvention, the equation relating loading dose to maintenance rate willrepresent a linear proportion or interpolation based on the loading doseand maintenance rate ranges suggested by the supplier and still morespecifically based on the maximum loading dose and maintenance ratesuggested by the supplier. These ranges may be therapy specific, forexample, a different proportion or interpolation based on the druglabel's recommended loading dose and maintenance rate for that therapywould be used if general anesthesia as opposed to conscious sedation wasthe objective. The loading dose calculation flow chart is provided inFIG. 2F where the calculation based on the maximum label dose is shownas program step 260.

After the loading dose (LD) has been calculated, the anesthetic deliverysystem (ADS) will automatically deliver it, prior to starting themaintenance rate (MR). As shown in FIG. 2B, the loading dose can beadministered in a rapid induction model or a controlled induction model(see program determination 262).

1. Rapid Induction

In one embodiment illustrated in program step 222 in FIG. 2B, the ADScan deliver the LD at the maximum pump rate. For the purpose ofillustration, 999 ml/hr will be used as the maximum pump rate. DC firstcalculates the time required (seconds) to deliver the LD at 999 ml/hr:LD_time=3600*LD/(10*999)where 3600 is the conversion from hours to seconds (sec/hr) and 10 isthe concentration of the propofol solution (mg/ml). The LD_time is thenconverted into sampling intervals. For the purpose of illustration only,a sampling interval of 1.5 seconds will be used:LD_intervals=LD_Time/1.5

If the number of LD_intervals is not an integer, then DC calculates theinfusion rate (ml/hr) for the last interval (program step 228) todeliver the remainder of the LD using the equation:IR _(—) LD_remain=999*Interval_remain+MR_ml/hr*(1−Interval_remain)where,MR_ml/hr=MR*W/166.67=Maintenance Rate in ml/hrInterval_remain=LD_intervals−INTEGER(LD_intervals)

Note that the 166.67 is the conversion based on 60 min/hr, and 1,000μg/mg, and 10 mg/ml (propofol concentration).

The ADS then delivers the loading dose for INTEGER(LD_Intervals) at apump rate 999 ml/hr, and then delivers at IR_LD_remain for one interval.This is shown if FIG. 2B in program steps 226 and 228. Immediatelyfollowing the completion of the LD, the ADS starts delivery of the MR(actually at a pump rate of MR_ml/hr).

2. Controlled Induction

In an alternative embodiment illustrated in FIG. 2B at program step 224,the ADS can deliver the LD over a specified period of time, with adecreasing ramp that culminates at the maintenance rate. For the purposeof illustration, 3 minutes (180 seconds) will be used as the ControlledInduction time. First, DC calculates the infusion rate (μg/kg/min)required if the LD were delivered at a constant rate over those 3minutes:Temp_rate=1000*LD/(W*3)where, 1000 is conversion from mg to μg

As shown in FIG. 3, the area of the rectangle (dashed line in FIG. 3)defined by the Controlled Induction period (180 seconds) and theTemp_rate equals the LD. For this embodiment, the objective is tocalculate a ramp, such that the area under the ramp is equal to the areaof the rectangle defined by the Temp_rate. This is accomplished withbasic geometry. First, since the ramp terminates into the MaintenanceRate (dotted line at 75 μg/kg/min in FIG. 3) at the end of theControlled Induction period, the area under the Maintenance Rate can beignored for the following analysis—so the focus can be on the areasabove the MR. Then, if the ramp is such that the height of the ramp isequal to two times the height of the rectangle (above the MR) then thearea under the ramp is equal to the area under the rectangle. This isillustrated in FIG. 3: A1=A2, therefore the area of the triangle equalsthe area of the rectangle.

The DC first calculates the difference (Delta) between the Temp_Rate andthe MR:Delta=Temp_rate−MRthen in this example, the starting rate (μg/kg/min) for the ramp wouldbe2*Deltaand the slope (μg/kg/min/min) of the ramp in this example would beSlope=2*Delta/3where 3 is the induction period. However, this assumes a continuousramp. The DC ramp is actually a series of decreasing steps (each stepdefined by the sampling interval, which is 1.5 seconds in thisillustration). The area under this “staircase” must equal the area underthe ramp, in order for the LD to be correct. The same geometricalprincipal applied above applies here as well, and is illustrated in FIG.4. If the height of each step is equal to the average height of the rampover the step interval the areas will be the same.

Therefore, the starting rate (μg/kg/min) for the ramp is more correctlyexpressed as:Start_(—) IR=MR+2*Delta−(Slope/2)/40where 40 is the number of samples taken over a minute (1.5 secondintervals)—converting the slope from “per minute” to “per interval.”

The ADS delivers the LD starting at Start_IR and then ramps down theinfusion rate, each sample, over the next 3 minutes:LD _(—) IR=Start_(—) IR−Slope*Interval_count/40Interval_count_(x)=Interval_count_(x-1)+1where, Interval_count is a counter tracking the progression of the 120samples in the 3 minute period. At the end of the 3 minutes the infusionrate will be equal to the MR selected by the user, and the ADS willcontinue to deliver the MR.

It is important to note that all the calculations are in μg/kg/min,therefore before sending the rate to the pump it must be converted intoml/hr. The standard equation for converting from μg/kg/min to ml/hr is:IR_ml/hr=IR*W/166.67

In another embodiment for the Controlled Induction, DC could simplydeliver the Temp_Rate over the entire time period, then switch to theMaintenance Rate. This embodiment is illustrated in FIG. 2B of the flowchart. In the illustrated embodiment, the system gives the clinician theoption in program step 220 of selecting between the rapid induction mode222 or the controlled induction mode 224.

The method described above basically portrays how anesthesiologists, whoare trained in pharmacokinetic principals, sedate a patient. The DC isadvantageous because it automatically correlates the loading dose withthe maintenance rate (or vice versa) so that only one variable is neededto compute the other. For example, whereas in the prior art, thephysician needed a value for both the loading dose and the maintenancerate in order to rapidly initiate and maintain sedation, a ADS using theDC is able to calculate the appropriate loading dose based on a givenmaintenance rate. Thus, by entering the desired maintenance rate for thepatient, DC automatically calculates the loading dose needed to rapidlybring the patient's level of sedation to the selected maintenance rate.The loading dose is administered followed by the constant infusion atthe specified maintenance rate.

Conversely, the DC can also calculate a maintenance rate based on agiven loading dose value.MR=75*LD/(0.5*W)

B. Adjusting Level of Sedation

DC also allows for rapid adjustment to a new level of sedation when theclinician programs a new maintenance rate. In prior methods of druginfusion, if an anesthesiologist intra-procedurally decides to changethe patient's level of sedation, he will typically adjust only theinfusion rate, and not deliver another loading dose. This results in aslower adjustment from the present level of sedation to the new level ofsedation. However, DC can calculate an incremental loading dose for eachchange in maintenance rate. This results in a significantly quickeradjustment because delivering an additional bolus rapidly brings thepatient to the new level of sedation.

1. Incremental and Cumulative Loading Dose

In accordance with the invention, a correlation is established betweenloading dose and maintenance rate. Based upon this correlation, bytracking the accumulated loading dose, the ADS can quickly define abolus or incremental loading dose that will rapidly produce a level ofsedation that is consistent with the new maintenance rate. The clinicianprograms changes in the level of sedation he or she desires by inputtinga new maintenance rate that the clinician associates with the desiredlevel of sedation. Each time a maintenance rate change is requested, DCwill calculate the loading dose required for the new maintenance ratebased on the equation above and then subtract the total loading dosespreviously given (cumulative loading dose—LD_cum) as shown in FIG. 2Fstep 262 to compute the incremental loading dose value to beadministered to the patient.Incremental LD=0.5*W*(MR_new/75)−LD_cum

Before starting the new maintenance rate, the ADS will deliver this“incremental” loading dose to rapidly bring the patient from the presentlevel of sedation to the new level, and then maintain this new level ofsedation at the new maintenance rate.

The Cumulative Loading Dose may be computed as shown in FIG. 2E by thefollowing formula:LD_cum_(x) =LD_cum_(x-1)+amount of LD delivered during sample

Thus, the loading dose needed to rapidly increase the patient from thepresent level of sedation to the new level of sedation, i.e. theincremental loading dose, is calculated by calculating an initiationloading dose for the new maintenance rate and then subtracting thecumulative loading dose already delivered to the patient as shown inFIG. 2F, step 262. FIG. 2E illustrates the calculation of the cumulativeloading dose. In the illustration the cumulative loading dose isadjusted to add the amount of loading dose added during a sampleinterval. Calculation of the cumulative loading dose when the additionof the incremental loading dose is made by the rapid induction method isshown at program step 252 in FIG. 2E. Alternatively, this addition canoccur using the controlled induction as shown in program step 250 inFIG. 2E. When the loading dose is negative, the cumulative loading doseis reduced as shown at 254.

For the purpose of illustration, assume that to achieve a level ofsedation corresponding to maintenance rate of 50 μg/kg/min requires aninitiation loading dose of 0.33 mg/kg, and to achieve a level ofsedation corresponding to maintenance rate of 75 μg/kg/min requires aninitiation loading dose of 0.50 mg/kg. When the drug is beingadministered at a current maintenance rate of 50 μg/kg/min and thephysician desires to increase the patient's level of sedation with amaintenance rate of 75 μg/kg/min, DC would calculate an incrementalloading dose of 0.50−0.33=0.17 to bring the patient to a level ofsedation corresponding to the new maintenance rate of 75 μg/kg/min.Essentially, the incremental loading dose required to bring the patientto the level of sedation corresponding to new maintenance rate iscalculated by taking the difference between the initiation loading doserequired to bring a patient to a specified maintenance rate (e.g.LD=0.50 mg/kg for MR=75 μg/kg/min) and the cumulative loading dosealready administered to the patient (present MR=50 μg/kg/min, LD was0.33 mg/kg). Thus, to bring the patient from MR=50 to MR=75, thecumulative LD administered to the patient for MR=50 (0.33 mg/kg) issubtracted from the initiation LD for MR=75 (0.50 mg/kg) to get theincremental loading dose of 0.17 mg/kg. Accordingly, an incrementalloading dose of 0.17 should be given to increase the patient from thepresent level of sedation to the new level of sedation. The new LD_(cum)would then be 0.50 mg/kg which would be used to calculate a newincremental loading dose if another new maintenance rate is desired.

The “administration” of the incremental loading dose during a procedurewhen a physician decides to increase the maintenance rate, differs fromwhen a physician decides to decrease the present maintenance rate asfurther described below.

2. Increase in Maintenance Rate: Rapid Induction

During the procedure, the physician may determine that the patient isunder-sedated and increase the maintenance rate. In order to rapidlybring the patient's level of sedation to the new level of sedation, anincremental loading dose will be delivered to the patient.

In the Rapid Induction embodiment, the ADS will deliver the LD asquickly as possible, setting the pump rate to a maximum rate (e.g., 999ml/hr) until the LD is delivered. However, unlike the initiation LD, inthis case DC must deliver the LD on top of an existing MR and theexisting infusion rate must be accounted for in the calculation of theLD time.

The formula to determine the length of time to deliver the LD at 999ml/hr is:LD_time=3600*LD/(10*(999−MR ml/hr))where MR_ml/hr=MR*W/166.67, and MR is not the new maintenance rate, butit is the existing maintenance rate, prior to the change. At the end ofthe LD, once the ADS starts delivering the new maintenance rate(MR_new), the variable will be reset. This is illustrated in FIG. 2F, atstep 268.LD_time is converted into intervals (again using 1.5 seconds for thisillustration):LD_intervals=LD_time/1.5

Again, if LD_intervals is not an integer, DC must calculate the infusionrate required to deliver the remainder of the LD during the next sampleinterval:IR _(—) LD_remain=999*Interval_remain+MR_new_ml/hr*(1−Interval_remain)where,Interval_remain=LD_intervals−INTEGER(LD_intervals)and MR_new_ml/hr is the new maintenance rate converted to ml/hr.

The ADS will deliver the loading dose at a pump rate of 999 ml/hr forINTEGER(LD_intervals) and then at an infusion rate of IR_LD_remain forone sample. After delivering the LD the ADS will set MR to MR_new, andbegin delivery of the new maintenance rate.

These equations are basically identical to the equations for the initialLoading Dose delivery. If at start up both LD_cum and MR are set tozero, and the initial maintenance rate is treated as MR_new, then thesame equation can be used for all Rapid Induction maintenance rateincreases.

3. Increase in Maintenance Rate: Controlled Induction

In the Controlled Induction embodiment the ADS will deliver the LD overthe specified time period (3 minutes for illustration) on top of theexisting MR. See step 269 in FIG. 2F. As with an initiation LD, DCcalculates infusion rate (μg/kg/min) required as if the LD is to bedelivered at a constant rate:Temp_rate=1000*LD/(W*3)+MR

Again the maintenance rate value is not the new maintenance rate(MR_new), but the rate prior to changing the maintenance rate. In thisway, the loading dose is being administered on top of the existingmaintenance rate.

DC then calculates the difference between this Temp_Rate and the MR_new:Delta=Temp_rate−MR_new

The starting rate (μg/kg/min) for the ramp is then:Start_(—) IR=MR_new+2*Delta−(Slope/2)40and the slope of the ramp (μg/kg/min/min) is:Slope=2*Delta/3

The ADS delivers the LD starting at Start_IR and then ramps down theinfusion rate, each sample, over the next 3 minutes:LD _(—) IR=Start_(—) IR−Slope*Interval_count/40Interval_count_(x)=Interval_count_(x-1)+1where, Interval_count is a counter tracking the progression of the 120samples in the 3 minute period. At the end of the 3 minutes the infusionrate will be equal to the MR_new, and DC will set MR=MR_new and continueto deliver the new maintenance rate.

These equations are similar to the equations for the initial LoadingDose delivery. If at start up both LD_cum and MR are set to equal zero,and the initial Maintenance Rate is set as MR_new then the same equationcan be used for all Three Minute Induction Maintenance Rate increases.

In an alternative embodiment the incremental LD can delivered at aconstant rate over the “controlled induction” period.

4. Decrease in Maintenance Rate

If the maintenance rate is decreased (e.g., if the clinician feels thepatient is over-sedated) the incremental loading dose will be negative.However, it is not possible to withdraw drugs from the patient.Calculation of a negative loading dose is shown in FIG. 2C. To simulatea negative loading dose, the DC calculates the period of time it wouldtake to deliver that negative dose at the existing maintenance ratebased on the formula:Zero_time=60*1000*LD/(MR*W)where, 1000 is a conversion from mg to μg, 60 is conversion from minutesto seconds, and MR is the existing maintenance rate prior to the change,not the new maintenance rate (MR_new). This is shown in FIG. 2F atprogram step 266. The cumulative loading dose is also decreased as shownin program step 254 in FIG. 2E.

This time is converted into sampling intervals. For the purpose ofillustration a sampling interval of 1.5 seconds will be used:Zero_intervals=Zero_time/1.5

Again, if Zero_intervals is not an integer, DC calculates the infusionrate required to deliver the remainder of the LD during the last sample:IR_zero_remain=MR_new_ml/hr*(1−Interval_remain)where,Interval_remain=Zero_intervals−INT(Zero_intervals)

The ADS will stop delivery of propofol for INT(Zero_intervals) and thenbegin infusing at an infusion rate of IR_zero_remain for one sample.After completing the LD, the ADS will set the maintenance rate toMR_new, and begin delivery of the new maintenance rate.

C. Intra-Procedure Bolus of Propofol

During the procedure the physician may decide that a transient increasein sedation is required. In this case, a physician typically administersa bolus that temporarily increases the patient's level of sedation. Forexample, if during a surgical procedure, a more sensitive part of theprocedure is about to be performed, the physician may give a bolus toraise the patient's level of sedation temporarily. In this case, themaintenance rate remains the same. When the transient increase insedation is over, the level of sedation returns to the level defined bythe previous maintenance rate. Because the maintenance rate remains thesame, an intra-procedure bolus does not affect the cumulative loadingdose calculation. FIG. 2A shows in program step 210 the determinationthat the bolus (PRN) is an intra-procedure addition that does not affectthe loading dose.

When the physician asks for a bolus, DC will calculate a fixed bolus(mg), for example:Bolus=0.25*W

In this example of DC, 0.25 was used as an illustration, however, anynumber from 0 to 0.5, which represents the loading dose rangerecommended by the pharmaceutical supplier, could have been chosen(exceeding 0.5 would mean that a single bolus would be larger than themaximum recommended LD for initiating sedation with propofol). Since thebolus will be delivered in addition to the existing maintenance rate theequations for delivering a Rapid Induction loading dose during anincrease in maintenance rate can be used here.Bolus_time=3600*Bolus/(10*(999−MR_ml/hr))

This time is converted into intervals at program step 212:Bolus_intervals=Bolus_time/1.5

Again, if Bolus_intervals is not an integer, in program step 214 DC cancalculate the infusion rate required to deliver the remainder of theBolus during the next sample:IR _(—) B_remain=999*Interval_remain+MR_ml/hr*(1−Interval_remain)where,Interval_remain=Bolus_intervals−INTEGER (Bolus_intervals)

The ADS will deliver the Bolus at a pump rate of 999 ml/hr for INTEGER(Bolus_intervals), and then at an infusion rate of IR_B_remain for onesample. After delivering the Bolus, the DC will renew the delivery ofthe maintenance rate.

In an alternative embodiment the bolus can be delivered over a fixedtime interval, similar to a Controlled Induction delivery of a LD duringa maintenance rate increase.

D. Examples

Non-limiting examples of various implementations of the above-describedembodiments of the invention are provided below:

1. If the physician changes the maintenance rate immediately after amaintenance rate change (i.e. during the delivery of a Rapid InductionLD), in one embodiment, DC calculates an “apparent maintenance rate”based on the Cumulative loading dose delivered at that time:MR_apparent=75*LD_cum/(0.5*W)

This calculation is used in program step 240 in FIG. 2D.

The cumulative loading dose here would be equivalent to the cumulativeloading dose at the old maintenance rate plus the total amount ofloading dose delivered during the Rapid Induction prior to when thephysician changed the maintenance rate during the Rapid Induction asshown in FIG. 2E program step 252.

In accordance with one embodiment, DC next treats this change as astandard rate change (either increase or decrease) from the apparentmaintenance rate to the new maintenance rate. The standard formulas asdiscussed above are used.

2. If the physician changes the maintenance rate during a ControlledInduction (for example, 3 minutes for illustration purposes), theloading dose will still be delivered in the original 3 minute period. Inthe embodiment where the LD is delivered at a constant rate over theControlled Induction period, a new constant infusion rate is calculated,that will deliver the new incremental LD over the remaining time.

In the embodiment where the Loading Dose is delivered via a decreasingramp, the Dosage Controller must recalculate a slope and initialinfusion rate. To accomplish this, DC uses a counter that is triggeredin the Controlled Induction mode. It is called Ramp_counter and isinitialized at 120 (180 minutes in 1.5 second intervals). Then theequations for the Temp_rate and Slope in the Controlled Induction modebecome:Temp_rate=1000*LD/(W*(3*Ramp_counter/120))+MRSlope=2*Delta/(3*Ramp_counter/120).

The rest of the equations may remain unchanged.

Every interval during the Controlled Induction Ramp_counter is decreasedby 1, reaching 0 at the end of the 3 minutes, and Interval_count isincreased by 1. If the physician changes the maintenance rate during theControlled Induction, the equation to calculate the new constant rateand slope uses the current value of the Ramp_counter—it is not reset to120. In this manner there is an immediate change to a new Start_IR,ramping down to the MR_new at a new slope. This holds for both rateincreases and decreases (depending on how much of the original loadingdose was delivered, there may still be some LD to deliver despite adecrease in the MR). If the calculated LD is negative, the DC switchedto the Time_zero mode.

In a further embodiment, the DC can be configured to require any changeduring a Controlled Induction to start a new 3 minute clock. In thiscase the original 3 Minute Induction equations would be used.

3. If a bolus is selected during delivery of a loading dose, the loadingdose can be interrupted as the ADS delivers the bolus. Immediately afterdelivering the bolus the loading dose is resumed where it left off.

4. If the maintenance rate is changed during the delivery of a bolus,the DC notes the maintenance rate change request, but continues with thedelivery of the bolus. Immediately after the bolus has been delivered,the DC switches into a new maintenance rate mode.

E. Supervisory Features

The concepts of the cumulative loading dose and the apparent maintenancerate also enable DC to be effectively integrated into a comprehensiveSupervisory Shell. A Supervisory Shell is a function embedded inautomated drug delivery systems that is designed to monitor drugdelivery based upon control parameters in addition to the maintenancerate and loading dose correlation discussed above. Elements of aSupervisory Shell can include (but are not limited to):

-   -   Infusion Rate Limits    -   Stopping drug delivery if adverse physiology or trends occur    -   Reducing drug delivery if certain conditions are met    -   Potentially increasing drug delivery under certain circumstances    -   Modifying controller parameters based on certain events (this        applies more to closed loop systems).

1. If a Supervisory Shell is designed to turn off drug infusion inresponse to adverse physiology, the DC can treat this as a normaldecrease in maintenance rate (stopping infusion is considered as a“decrease to zero”). A Zero_time will be calculated, and the cumulativeloading dose will be integrated down every interval. At the end of theZero_time the cumulative LD will equal zero. When the adverse eventclears (physiology returns to normal) the clinician will likelyre-establish drug infusion at a new maintenance rate. If this occursprior to the end of the Zero_time, the DC may treat it as a change in MRfrom the apparent MR (at the time the clinician decided to re-startinfusion) to the new MR. If the new MR is greater than the apparent MRit will be treated as a MR increase. If the new MR is less than theapparent MR it will be treated as a decrease (negative LD).

The clinician can choose either a Rapid or a Controlled Induction,however, if the LD is negative DC defaults to the Time_zero format. Inaddition, the clinician does not necessarily have to wait until theadverse physiology clears before re-starting drug delivery.

2. If the adverse event occurred during the delivery of a loading doseand the Supervisory Shell stopped drug delivery DC would use theapparent MR at the time the infusion was stopped, to calculate theZero_time.

3. A Supervisory Shell may be designed to reduce drug delivery inresponse to certain conditions—such as adverse trends. If theSupervisory Shell simply requests a fixed reduction (say 20% forexample) in the maintenance rate DC will handle this as a standard MRdecrease. An alternative way to integrate DC within a Supervisory Shellto reduce infusion rate in response to an adverse trend, is to takeadvantage of the apparent maintenance rate concept and tune the size ofthe infusion rate reduction to the severity of the patient's condition,as indicated by the trend. Specifically, upon detecting worseningphysiology the Supervisory Shell can instruct DC to set the MR to zero.This will cause DC to calculate a Time_zero and begin integrating downthe cumulative LD. When the condition clears (physiology returns tonormal) the Supervisory Shell can inform DC to re-establish drugdelivery at the apparent MR (which exists at the time the physiologyreturns to normal). In this manner, the longer the patient's physiologyis trending poorly, the larger the reduction in the infusion rate.

4. A Supervisory Shell may also be designed to temporarily stop drugdelivery if it detects a correctable problem within the ADS. Theseproblems could include (but not limited to) a dislodged pulse oximeterprobe, a disconnected ECG lead, air-in-line detected in the infusionline, or IV bag/vial empty. If the Supervisory Shell stops delivery ofdrug in response to such a problem, DC first saves the presentmaintenance rate then performs a decrease in maintenance rate, with thenew MR being zero. When the clinician corrects the problem, DCcalculates the apparent maintenance rate based on the cumulative loadingdose at the time the problem is corrected. Then DC performs an increasein maintenance rate (in the Rapid Induction mode preferably) from theapparent maintenance rate to the saved maintenance rate.

Without the concepts of the cumulative loading dose and the apparentmaintenance rate, a drug delivery system would have to rely on simplechanges to the maintenance rate. There would not be any loading doses(negative or positive) enabling the rapid achievement of the new levelof sedation. Therefore, there could be extended periods of time when thepatient is inadequately cared for.

F. Integration of DC and an Automated Responsiveness Monitor

Due to patient-to-patient variability IV drugs are typically titrated toclinical effect—the clinician must tune the infusion rate to achieve thetarget effect on each individual patient. Further, as the patient'sneeds change during the course of a medical procedure, the clinicianwill have to titrate the drug to maintain a desired target effect. Forwell-characterized physiologic parameters, such as blood pressure, thereare continuous monitors that a fully automated drug delivery system canuse to close-theloop and automatically perform this titration for theclinician. For most physiologic parameters the “loop” cannot beclosed—this includes sedation/anesthesia.

In one embodiment the ADS may include a means of assessing a patient'slevel of sedation—the Automated Responsiveness Monitor (ARM). Integratedwith the ARM and a Supervisory Shell, the DC will enable the clinicianto more easily titrate the delivery of propofol to each individualpatient. One method of using ARM comprises applying a vibration stimulior request for a predetermined response to the patient; instructing thepatient to respond to the vibration stimuli; and monitoring thepatient's response to the vibration stimuli. This action is repeated ata predetermined interval throughout the medical procedure

The use of ARM to assess a patient's level of sedation is described indetail in commonly assigned U.S. patent application Ser. No. 10/674,160filed Sep. 29, 2003 which is herein incorporated by reference. Asdescribed in the applications, there are many methods and apparatusesassociated with ARM. In sum, ARM is a patient response system that sendsvarious requests to a patient to receive a patient's response and thenanalyzes the patient's responses to the requests. By analyzing thepatient's responses, the patient's level of sedation can be determined.An example of how ARM works is shown in the drawings. FIG. 2 illustratesa conscious sedation system 100 including a controller 102 and aresponse testing apparatus 104. The controller 102 generates a requestfor a predetermined response from a patient 106 and analyses at least aresponse generated by the patient 106 to the request to determine alevel of sedation of the patient 106. The response testing apparatus 104includes a request assembly 108 and a response assembly 110. The requestassembly 108 communicates to the patient 106 the request generated bythe controller 102. The response assembly 110 is used by the patient 106to generate the response and communicates the response to the controller102. Example of response assemblies particularly useful herein are handgrip assemblies as described in detail in commonly assigned patentapplication Ser. No. 10/674,160 entitled Response Testing for ConsciousSedation Involving Hand Grip Dynamics filed on Sep. 29, 2003 (attydocket 451231-017). The response assembly includes a handpiece whichsenses a dynamic variable of a hand grip response made by the patient tothe request and communicates the dynamic variable to the controllerwhich analyzes at least the dynamic variable to determine a level ofsedation of the patient.

One method of integrating DC with the ARM and a Supervisory Shell is tolimit maintenance rate increases based on the patient's responsiveness.For example, if the patient is unresponsive to ARM, the system will notallow the user to increase the MR, but if the patient is responsivethere would be no ARM linked limits on increasing the MR. Alternatively,maintenance rate increase limits can be based on the patient's level ofresponsiveness. For example, if the patient responds to the stimuliwithin 5 seconds, the MR might be increased by 30 μg/kg/min in the caseof propofol, if the response occurs between 5 and 10 seconds the MR canbe increased by 20 μg/kg/min, and if the response occurs in greater than10 seconds the MR can only be increased by a limited amount such as 10μg/kg/min. This control function is illustrated in the flow chartprovided as FIG. 21 where control steps 290, 292 and 294 correspondrespectively to MR increases triggered by ARM response times of lessthan 5, 5 to 10 and 10 or more seconds.

Furthermore, the patient's response to ARM, or more specifically, lossof ARM response may be used as a Supervisory Shell feature in monitoringand adjusting the maintenance rate especially for long procedures.According to PK principals, over time even with a constant infusionrate, the concentration of a drug in the body will gradually increase.This can lead to unexpected over-dosage, and accompanying adverseevents. Propofol labeling calls for a reduction in infusion rate 15-20minutes after initiating a Maintenance Rate infusion. A SupervisoryShell, integrated into the DC can automatically perform this suggestedreduction effectively maintaining a safe level of sedation. In oneembodiment, as long as the patient is responsive to ARM, the integratedsystem will not perform an automatic reduction. However, after 15minutes of continuous non-responsiveness, the system can reduce themaintenance bate by a fixed amount (5% for example). This is repeatedevery 15 minutes, as long as the patient remains non-responsive to ARM.As soon as the patient regains responsiveness the reductions arestopped. Should the patient lose responsiveness again, for 15 continuousminutes the reductions will start again. By using DC of this invention,these MR reductions will rapidly and effectively reduce the patient'slevel of sedation. Although 15 minutes was used in the above discussion,the amount of time before triggering a reduction in infusion can vary,and should be selected based on the pharmacokinetics of the drug beingdelivered.

The above discussion centers on DC and the delivery of propofol.However, the concept of DC can be applied to any intravenous drug. Theequations will have to be adjusted to account for differentpharmacokinetics (loading dose/maintenance rate relationships) and adifferent measure of “effect” will be required for non-sedatives.

G. Integration of DC and ARM with Patient Tuned Sedation

A further embodiment incorporates a patient-tuned sedation feature withDC. Since differences in effective analgesia or anesthesia dosages canbe dramatic even among physically similar patients who are subjected tovery similar pain-producing circumstances, it could be desirable todevelop a system that incorporates patient input in the delivery of thedrugs. The concept is to include the benefits of patient controlledsedation with the benefits of DC.

With regard to the level of analgesia or anesthesia that is needed by aparticular patient at a particular time, it often has been suggestedthat the “best” pain expert for a particular patient is the patienthimself or herself—as opposed to the patient's physician. Whilephysicians may have the knowledge and experience that is needed todetermine a suitable dosage range to meet the needs of a particularpatient, it tends to be the patient, not the physician, who is the bestjudge of the dosage within the physician-set range that best serves theneeds of the patient at a particular time and under the circumstances ofthe moment. The effectiveness of the administration of analgesia oranesthesia often can be enhanced when the dosing of the drug is beingcontrolled by the patient—with safety considerations being kept in mindto prevent overdose. Accordingly, it is desired to provide a systemwhich combines the benefits of DC with the benefits of patientcontrolled sedation.

The system in this embodiment may also incorporate the advantages of DCand ARM with advantages of patient controlled sedation to form anotherembodiment of the present invention—Patient Tuned System (PTS). Inpatient tuned sedation, the patient, with an ARM-like device, is actingas the depth of sedation sensor, essentially, closing the loop onsedation. The system would include all of the patient monitors currentlyin the sedation delivery system such as ECG, capnometry, pulse oximetry,and NIBP.

In one embodiment, the level of sedation that is desired for theAnesthetic Delivery System is the transition between moderate and deepsedation. This transition point is well defined by the patient's loss ofresponsiveness to ARM. The patient's loss of responsiveness to ARMcorresponds with the point where a patient can no longer dose himselfwith a patient tuned sedation system. Essentially, the patient'sresponsiveness to ARM acts as a dose limiter so that when the patientloses responsiveness, the patient can't send any response to delivermore drug. Furthermore, there is a lock-out period that follows apatient's response, such as pressing a button to deliver additionaldrugs, to prevent the patient from overdosing himself.

In an embodiment of the invention, the Patient Tuned Sedation starts byhaving the clinician enter a “ballpark” maintenance rate along with thepatient's weight. The system would begin by delivering an initiationloading dose calculated from DC in accordance with the invention. Aftera specified time period, typically 90 seconds, the ARM-like device sendsa request for a patient's response. The request may be, for example, anaudible signal such as “Squeeze your hand if you are feelingdiscomfort.” The message may be repeated every 60 seconds.

If the patient responds quickly, for example within 3 seconds of themessage, to the request by squeezing his hand, the PTS will increase themaintenance rate by 10 μg/kg/min, utilizing DC to rapidly achieve thenew sedation level. At this point, the PTS will be locked out fromincreasing the maintenance rate for 60 seconds regardless of how manytimes the patient squeezes his hand. This acts as a safety precaution toprevent the patient from over-sedation. If the patient responds, lessquickly, for example, between 3 and 10 seconds, the PTS would increasethe maintenance rate by 5 μg/kg/min. If it took the patient a greatertime to respond, for example more than 10 seconds, the PTS would notincrease the maintenance rate, but would rather deliver a small bolus(˜0.025 mg/kg).

In another embodiment, the maintenance rate increase could be larger,say 25 μg/kg/min for a response within 3 seconds, 12 μg/kg/min forresponses between 3 and 10 seconds and a 0.1 mg/kg bolus for longerresponses, but the lock-out period would be longer, on the order of 3 to5 minutes.

If the patient does not respond within an allotted time (15 seconds),the PTS would not deliver any additional drug. Further, if the patientdoes not respond during 3 consecutive queries, the PTS would begin aslow decrease in the maintenance rate, for example, 5% every 15 minutes.This is intended to keep the non-responsive or deeply sedated patientfrom entering a state of general anesthesia.

Accordingly, by using a patient tuned sedation system, the patient actsas the depth of sedation monitor, essentially closing the loop onsedation.

Having described the invention in detail and by reference to specificembodiments thereof, it will be apparent that modifications andvariations are possible without departing from the spirit and scope ofthe invention as defined by the following claims. The variousembodiments described herein may be performed separately or together inany combination.

1. A method for delivering intravenous drugs to a patient comprising:programming a drug delivery system including a controller and aninfusion pump with a maintenance rate or a loading dose for a drug;causing the drug delivery system to: (a) calculate a loading dose basedon the maintenance rate or a maintenance rate based on the loading dose;(b) administer the loading dose of the drug to the patient to rapidlyachieve a desired level of effect; and (c) administer the drug at afirst maintenance rate to maintain the level of effect.
 2. The method ofclaim 1 wherein the step of calculating a loading dose based on themaintenance rate or a maintenance rate based on the loading dose isbased on a formula that correlates the maintenance rate and the loadingdose recommended by the drug supplier.
 3. The method of claim 2 whereinthe formula is based upon a linear interpolation of the maximum loadingdose and the maximum maintenance rate recommend by the drug supplier. 4.The method of claim 3 wherein the drug is propofol and the formula is:LD=0.5*W*(MR/75) where, LD=Loading Dose (mg), MR=Maintenance Rate(μg/kg/min), W=Weight (kg) of the patient.
 5. The method of claim 1wherein the step of administering the loading dose is performed using aninfusion pump at an infusion rate approximately equal to the maximuminfusion rate of the pump.
 6. The method of claim 1 wherein the step ofadministering the loading dose is conducted by administering the loadingdose over a predetermined period.
 7. The method of claim 1 wherein thedrug delivery systems tracks the cumulative loading dose administered tothe patient, wherein the cumulative loading dose is calculated based onthe formula:LD_cum_(x) =LD_cum_(n-1)+ amount of LD currently delivered in sample x8. The method of claim 1 wherein the method includes the additionalsteps of: programming the drug delivery system with a second maintenancerate whereupon the system: (a) calculates an incremental loading dosefor the drug based on the second maintenance rate (b) administers theincremental loading dose to the patient to rapidly achieve the newdesired level of effect; and (c) administers the drug at the secondmaintenance rate to maintain the new level of effect.
 9. The method ofclaim 8 wherein the incremental loading dose is calculated for thesecond maintenance rate and the cumulative loading dose based on aformula that correlates the maintenance rate and the loading doserecommended by the drug supplier
 10. The method of claim 9 wherein thedrug is propofol and the incremental loading dose is calculated from thesecond maintenance rate and the cumulative loading dose based on theformula:Incremental LD=0.5*W*(MR_new/75)−LD_cum
 11. The method of claim 9wherein the second maintenance rate is increased from the firstmaintenance rate.
 12. The method of claim 11 wherein the drug isadministered to the patient using an infusion pump and the incrementalloading dose is administered at a rate approximately equal to themaximum infusion rate of the pump.
 13. The method of claim 11 whereinthe step of administering the incremental loading dose is conducted byadministering the incremental loading dose over a predetermined period.14. The method of claim 9 wherein the second maintenance rate is lessthan the first maintenance rate.
 15. The method of claim 14 wherein theincremental loading dose is a negative loading dose.
 16. The method ofclaim 15 wherein the negative loading dose is administered by setting ainfusion rate to zero for a period of time.
 17. The method of claim 16wherein the zero period of time is calculated based on the incrementalloading dose.
 18. The method of claim 17 wherein the zero time period iscalculated using the formula:Zero_time=60*1000*LD/(MR*W)
 19. The method of claim 1 wherein the methodfurther includes the step of administering a transient bolus of the drugto temporarily increase in the patient's level of effect.
 20. The methodof claim 1 wherein the steps of administering are discontinued ifadverse physiology is detected